chr7-137015556-G-A

Position:

chr7-137015556-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001006630.2(CHRM2):c.691G>A(p.Val231Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,612,814 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 27 hom. )

Consequence

CHRM2
NM_001006630.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

CHRM2 (HGNC:1951): (cholinergic receptor muscarinic 2) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine to these receptors and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 2 is involved in mediation of bradycardia and a decrease in cardiac contractility. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

CHRM2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066742003).

BP6

Variant 7-137015556-G-A is Benign according to our data. Variant chr7-137015556-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM2	NM_001006630.2 linkuse as main transcript	c.691G>A	p.Val231Ile	missense_variant	4/4	ENST00000680005.1	NP_001006631.1
LOC349160	NR_046103.1 linkuse as main transcript	n.341+17238C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM2	ENST00000680005.1 linkuse as main transcript	c.691G>A	p.Val231Ile	missense_variant	4/4		NM_001006630.2	ENSP00000505686	P1
	ENST00000586239.5 linkuse as main transcript	n.273+17238C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

525

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000585

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00425

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00556

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00343

AC:

856

AN:

249462

Hom.:

AF XY:

0.00332

AC XY:

447

AN XY:

134830

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00568

Gnomad EAS exome

AF:

0.000552

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00497

Gnomad NFE exome

AF:

0.00525

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00568

AC:

8294

AN:

1460854

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

3905

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00475

Gnomad4 EAS exome

AF:

0.000608

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00445

Gnomad4 NFE exome

AF:

0.00670

Gnomad4 OTH exome

AF:

0.00615

GnomAD4 genome

AF:

0.00345

AC:

525

AN:

151960

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

230

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.000586

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00425

Gnomad4 NFE

AF:

0.00556

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00486

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00296

AC:

359

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2015	p.Val231Ile in exon 5 of CHRM2: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (299/65916) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs76394680). -

Dilated Cardiomyopathy, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.053

T;T;T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

.;.;.;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0067

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.67

N;N;N;N

MutationTaster

Benign

0.93

D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.18

N;N;N;N

REVEL

Benign

0.047

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.061

MVP

0.87

MPC

0.45

ClinPred

0.0079

GERP RS

5.4

Varity_R

0.16

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over